title: When pharmacodynamics trump costs: an antimicrobial stewardship program's approach to selecting optimal antimicrobial agents.
abstract: BACKGROUND
  Treatment of Pseudomonas aeruginosa infections is increasingly challenging because of escalating resistance. Antimicrobial stewardship programs provide guidance for clinicians regarding use of the most appropriate antimicrobial at the right dose, duration, and route in addition to being cost-effective. Optimizing antimicrobial therapy by using pharmacokinetic/pharmacodynamic principles such as extending time above the MIC is 1 stewardship strategy to reduce antimicrobial resistance.
  
  
  OBJECTIVE
  The goal of this study was to evaluate our current dosing strategy for cefepime and the formulary carbapenem (imipenem) compared with meropenem and doripenem to determine the best dosing strategy for achieving maximal pharmacodynamic activity against an institution-specific population of P aeruginosa isolates.
  
  
  METHODS
  Consecutive, nonduplicate, blood (n = 39) or bronchial alveolar lavage (n = 25) isolates of P aeruginosa from adult, hospitalized (2009-2010) critically ill patients underwent MIC testing by using broth microdilution. A pharmacokinetic model was developed and used with Monte Carlo simulation to evaluate the ability of imipenem, meropenem, doripenem, and cefepime to achieve optimal bactericidal activity as varying doses infused over standard infusions (SIs; 0.5-1 hour) or prolonged infusions (PIs; 3-4 hours). A regimen was defined as optimal if the cumulative fraction response (CFR) was ≥90%.
  
  
  RESULTS
  None of the imipenem regimens modeled as SI or PI achieved a CFR ≥90%. Meropenem at 1 to 2 g q8h PI achieved a CFR ≥90%. Doripenem 0.5, 1, or 2 g q8h PI achieved a CFR ≥90%. The only cefepime regimen that achieved a CFR ≥90% was 2 g q8h PI. Overall susceptibility rates to P aeruginosa were highest with cefepime (91%), followed by meropenem (83%), doripenem (78%), and imipenem (72%). Our antimicrobial stewardship programs recommended switching from imipenem to doripenem 0.5g q8h PI, which was 36% more costly in drug acquisition costs. Cefepime dosing was increased from 2 g q12h SI to 2 g q8h PI, a 52% increase in drug acquisition cost.
  
  
  CONCLUSIONS
  Antimicrobial stewardship programs should consider pharmacodynamic modeling to select the optimal dosing strategies to guide therapy in an era of escalating antimicrobial resistance. Using the percent susceptibility alone can be misleading and ultimately the most expensive if the patient fails to respond.
authors.affiliation: Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, USA. debbie.goff@osumc.edu
authors.forename: Debra A
authors.initials: DA
authors.lastname: Goff
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000191:economics / Q000493:pharmacokinetics / Q000494:pharmacology; D015780:Carbapenems / Q000008:administration & dosage* / Q000191:economics / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000077723:Cefepime; D002511:Cephalosporins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000077726:Doripenem; D016527:Drug Costs; D006801:Humans; D015378:Imipenem / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000302:isolation & purification; D013845:Thienamycins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D002511:Cephalosporins; D013845:Thienamycins; D015378:Imipenem; D000077723:Cefepime; D000077726:Doripenem; D000077731:Meropenem